Economic Evaluation of Denosumab Compared with Zoledronic Acid in Hormone-Refractory Prostate Cancer Patients with Bone Metastases

BACKGROUND: Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. OBJECTIVES: To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. METHODS: An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first SRE, subsequent SREs, disease progression, and death were primarily derived from the results of the Phase 3 clinical trial and were supplemented with published literature. The model assumed that a maximum of 1 SRE could occur in each cycle. Drug costs included wholesale acquisition cost, health care professional costs associated with drug administration, and drug monitoring costs, if applicable. Nondrug costs included incremental costs associated with disease progression, costs associated with SREs, and terminal care costs, which were derived from the literature. Adverse event (AE) costs were estimated based on the incidence rates reported in the Phase 3 trial. Resource utilization associated with AEs was estimated based on consultation with a senior medical director employed by the study sponsor. All costs were presented in 2010 dollars. The base case estimated the incremental total cost per SRE avoided over a 1-year time horizon. Results for a 3-year time horizon were also estimated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the model. RESULTS: In the base case, the total per patient costs incurred over 1 year were estimated at $35,341 ($19,230 drug costs and $16,111 nondrug costs) for denosumab and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for zoledronic acid, with an incremental total direct cost of $7,813 for denosumab. The estimated numbers of SREs per patient during the 1-year period were 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of -0.11 in the denosumab arm. The estimated incremental total direct costs per SRE avoided with the use of denosumab instead of zoledronic acid were $71,027 for 1 year and $51,319 for 3 years. The 1-way sensitivity analysis indicated that the results were sensitive to the drug costs, median time to first SRE, and increased risk of SRE associated with disease progression. Results of the PSA showed that based on willingness-to-pay thresholds of $70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the cases at 1 year, respectively, and 79.0%, 49.8%, and 4.1% of the cases at 3 years, respectively. CONCLUSIONS: Although denosumab has demonstrated benefits over zoledronic acid in preventing or delaying SREs in a Phase 3 trial, it may be a costly alternative to zoledronic acid from a U.S. payer perspective.

• Bone metastases are prevalent in patients with hormone-refractory prostate cancer and are associated with substantial economic burden in the United States ($1.9 billion in 2004). • Skeletal-related events (SREs) are frequently seen in hormonerefractory prostate cancer patients with bone metastases. Lage et al. (2008) found that approximately one-half of patients with hormone-refractory prostate cancer and bone metastases in their study sample had at least 1 SRE. SREs are associated with increased health care costs and decreased quality of life. • Reed et al. (2004) showed that compared with placebo, zoledronic acid was associated with an incremental cost per SRE ABSTRACT BACKGROUND: Bone metastases are common in patients with hormonerefractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer.
OBJECTIVE: To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormonerefractory prostate cancer.
METHODS: An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1-and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first SRE, subsequent SREs, disease progression, and death were primarily derived from the results of the Phase 3 clinical trial and were supplemented with published literature. The model assumed that a maximum of 1 SRE could occur in each cycle. Drug costs included wholesale acquisition cost, health care professional costs associated with drug administration, and drug monitoring costs, if applicable. Nondrug costs included incremental costs associated with disease progression, costs associated with SREs, and terminal care costs, which were derived from the literature. Adverse event (AE) costs were estimated based on the incidence rates reported in the Phase 3 trial. Resource utilization associated with AEs was estimated based on consultation with a senior medical director employed by the study sponsor. All costs were presented in 2010 dollars. The base case estimated the incremental total cost per SRE avoided over a 1-year time horizon. Results for a 3-year time horizon were also estimated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the model. RESULTS: In the base case, the total per patient costs incurred over 1 year

R E S E A R C H
were estimated at $35,341 ($19,230 drug costs and $16,111 nondrug costs) for denosumab and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for zoledronic acid, with an incremental total direct cost of $7,813 for denosumab. The estimated numbers of SREs per patient during the 1-year period were 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of -0.11 in the denosumab arm. The estimated incremental total direct costs per SRE avoided with the use of denosumab instead of zoledronic acid were $71,027 for 1 year and $51,319 for 3 years. The 1-way sensitivity analysis indicated that the results were sensitive to the drug costs, median time to first SRE, and increased risk of SRE associated with disease progression. Results of the PSA showed that based on willingness-to-pay thresholds of $70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the cases at 1 year, respectively, and 79.0%, 49.8%, and 4.1% of the cases at 3 years, respectively. patients with bone metastases may lead to substantial benefits from the perspectives of both patients and payers.
The most widely used treatment in the prevention of SREs in patients with hormone-refractory prostate cancer is zoledronic acid (Zometa), a bisphosphonate that was approved by the U.S. Food and Drug Administration (FDA) in 2002. 7,8 A large randomized placebo-controlled trial found that zoledronic acid 4 milligrams (mg) administered every 3 weeks for 15 months was efficacious in preventing SREs and well tolerated in hormonerefractory prostate cancer patients with bone metastases. 9 In that study, patients in the zoledronic acid 4 mg treatment arm had a lower rate of SREs compared with placebo (33.2% vs. 44.2%, respectively, P = 0.021) and a longer median time to first SRE (not reached vs. 321 days, respectively, P = 0.011), compared with patients in the placebo arm. A subsequent analysis based on the same trial showed that, among all randomized patients, those receiving zoledronic acid 4 mg had a lower rate of having a second on-study SRE compared with placebo (21% vs. 31%, respectively, P = 0.017) and a delayed median time to second SRE (not reached vs. 449 days, respectively P = 0.006). 10 In a pharmacoeconomic analysis from a payer perspective, Reed et al. (2004) estimated that zoledronic acid compared with placebo was associated with an incremental cost per SRE avoided of $12,300 and incremental cost per quality-adjusted life year (QALY) of $159,200 among patients with hormonerefractory prostate cancer with bone metastases. 6 Denosumab (Xgeva) was approved by the FDA in November 2010 for the prevention of SREs in patients with solid tumors. 11 Denosumab is a fully human monoclonal antibody that inhibits osteoclastic-mediated bone resorption by binding to the osteoblast-produced antireceptor activator of nuclear factorκB ligand (RANKL) antibody. By inhibiting the action of RANKL, denosumab decreases bone resorption and turnover. 12,13 The efficacy and tolerability of denosumab versus zoledronic acid were evaluated in a randomized Phase 3 trial (NCT00321620, Amgen) in men with hormone-refractory prostate cancer with bone metastases. In the trial, 1,904 hormone-refractory prostate cancer patients with bone metastasis were randomized to 1 of the 2 treatment arms: subcutaneous denosumab 120 mg + intravenous placebo every 4 weeks and subcutaneous placebo + intravenous zoledronic acid 4 mg every 4 weeks. The results showed that denosumab was superior in delaying time to first on-study SRE compared with zoledronic acid (median 20.7 months vs. 17.1 months, respectively, hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.71-0.95, P = 0.008) and time to first and subsequent SREs (HR = 0.82, 95% CI = 0.71-0.94, P = 0.004). However, overall survival (HR = 1.03, P = 0.650) and disease progression (HR = 1.06, P = 0.300) were balanced between the 2 treatment arms. In addition, no significant difference was observed in the concentration of prostate-specific antigen between the treatment arms during the study. The safety results were similar between the zoledronic acid and P rostate cancer is the most common nonskin cancer and the second most common cause of cancer death in men in the United States, with 1 in 6 men developing prostate cancer during their lifetimes and 1 in 36 dying from the disease. 1 Prostate cancer places a substantial economic burden on health care systems. National expenditures in the United States for continuing care related to prostate cancer are estimated at over $6 billion in 2010 and are expected to rise to almost $9 billion by 2020. 2 Costs associated with bone metastases in prostate cancer appear to be a major contributor to the high costs of prostate cancer and were estimated at $1.9 billion in 2004 dollars. 3 Bone metastases are common in patients with hormonerefractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. 4 In particular, metastatic bone may lead to pathologic fractures and spinal cord compression and may require surgery or radiation therapy. Skeletal-related events (SREs), including pathologic fracture, spinal cord compression, bone surgery, and radiation therapy to the bone, present a significant challenge to the management of prostate cancer. A recent claims-based analysis by Lage et al. (2008) found that approximately one-half of patients with prostate cancer and bone metastases in their sample experienced at least 1 SRE. 5 In addition, SREs have been shown to be associated with decreased quality of life 6 and increased health care costs in prostate cancer patients with bone metastases. 5 A pharmacoeconomic analysis conducted alongside a randomized clinical trial showed that among patients with prostate cancer, health utility scores as measured by EuroQoL-5D (EQ-5D) were significantly lower for patients with an SRE than for those without an SRE during the same time frame. 6 Furthermore, in the United States from May 2000 through March 2005, the mean annual charge in prostate cancer patients with bone metastases and 1 or more SREs was estimated at $12,469 per patient in 2006 dollars. 5 Therefore, reducing or delaying the presence of SREs in prostate cancer • This is the first study to compare the cost-effectiveness of denosumab versus zoledronic acid in patients with hormone-refractory prostate cancer with bone metastases. • This economic model, constructed using data from a Phase 3 head-to-head clinical trial, predicted 0.49 and 0.60 SREs per patient treated with denosumab and zoledronic acid, respectively, during the first year of treatment. • After accounting for drug and nondrug costs, use of denosumab rather than zoledronic acid was associated with estimated incremental total direct costs per SRE avoided of $71,027 and $51,319 over 1-and 3-year time periods, respectively, in hormone-refractory prostate cancer patients with bone metastases.

What this study adds
denosumab treatment arms, with lower rate of hypocalcemia (6% vs. 13%, respectively, P < 0.001) and Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 adverse events (66% vs. 72%, respectively, P = 0.01). 14 While denosumab is efficacious in the prevention of SREs in patients with hormone-refractory prostate cancer, the drug acquisition cost is higher for denosumab than for zoledronic acid ($1,650 versus $878, respectively, per dose in the United States). 15 Hence, it is important to consider the economic implications of this cost difference from a payer perspective. 16 Currently, there are no studies to inform U.S. payers regarding the economic value of denosumab versus zoledronic acid in prostate cancer patients with bone metastases. In order to address this gap, a Markov decision model was developed to assess the cost-effectiveness of denosumab versus zoledronic acid in the prevention of SREs in hormone-refractory prostate cancer patients with bone metastases.
In the Phase 3 trial, SRE development was selected as the primary efficacy endpoint, and denosumab and zoledronic acid had similar rates of disease progression and overall survival. Therefore, this study used total incremental cost per SRE avoided as the cost-effectiveness measure, which was used in previous economic analyses of treatments that prevent and delay SREs in cancer patients. 6,17 Thus, the primary objective of this study was to compare the cost per SRE avoided for denosumab compared with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer.

■■ Methods Model Structure
We developed a Markov decision model from the U.S. health care payer perspective with a 1-year time horizon as the base case. The time horizon was chosen for 2 reasons: (1) this was the closest approximation to the median duration of the Phase 3 trial; 14 and (2) U.S. payers typically prefer a shorter time horizon for economic evaluations. 18 A 3-year time horizon was also included as a co-primary outcome because some payers may be interested in the results with a longer time frame. We chose the 1-year instead of 3-year time horizon as the base case because zoledronic acid (Zometa) is expected to be available in a less expensive generic form by March 2013.
Direct costs, including treatment drug costs and nondrug costs as well as effectiveness outcomes (i.e., number of SREs), were estimated over the 1-and 3-year periods after denosumab or zoledronic acid therapy initiation. The incremental costeffectiveness ratio (ICER) was measured as total incremental cost per SRE avoided. The SREs, as defined in the Phase 3 trial, included pathologic fracture, spinal cord compression, radiation to bone, or surgery to bone. 14 As mentioned previously, the effectiveness outcome was chosen to be consistent with the primary outcome in the Phase 3 trial. The trial was designed to examine superiority of denosumab compared with zoledronic acid in time to first SRE and time to first and subsequent SREs after the primary endpoint of noninferiority in time to first SRE was met. Disease progression and overall survival were reported; however, since the trial did not detect a difference in these outcomes between the 2 treatment arms, they were not considered as endpoints in the model. 14 The Markov model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death ( Figure 1). We included disease progression because it has been shown to increase the risk of SREs. 19 The length of each Markov cycle is one-quarter year (i.e., 13 weeks). The cycle length was selected to allow enough time to distinguish between 2 separate SREs, with the assumption that no more than 1 SRE could occur within each cycle. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned between the 9 health states at the beginning of each model cycle. All patients were assumed to start with the state of no SRE, no history of SRE in the trial, and no progression. Patients were assumed to experience disease progression before transitioning to death. Transitional probabilities among these states and state-specific costs were estimated using the model inputs extracted from the existing literature and publicly available data. Cumulative direct costs and the total number of SREs were estimated for each arm over the 1-and 3-year periods. A discount rate of 3% was applied for both cost and effectiveness outcomes in the base case.

Transitional Probabilities
Transitional probabilities among different states were derived primarily from the efficacy results of the Phase 3 head-to-head clinical trial comparing denosumab and zoledronic acid. 14 They were supplemented by data from the literature.

Transitional Probability to First On-Study SRE Among
Patients Without Progression. Probabilities of having a first SRE for zoledronic acid and denosumab in each cycle were estimated based on the reported median times to first SRE in the Phase 3 trial, which were 17.1 and 20.7 months for zoledronic acid and denosumab, respectively. 14 Assuming constant hazards, the study estimated the probabilities at 11.5% for zoledronic acid and 9.6% for denosumab. The assumption was made because primary patient-level data were not available to the researchers to accurately and reliably estimate the parameters of different functions, such as Weibull. In order to assess the potential bias of using median time instead of all data points, sensitivity analyses were conducted using the transitional probabilities estimated at 3, 6, 12, and 27 months.

Transitional Probability to a Subsequent SRE Among
Patients Without Progression. Because the Phase 3 trial did not report median time from a previous SRE to a subsequent SRE, the probability of having a subsequent SRE for zoledronic acid was derived by calibrating the total number of SREs (0.6) at month 12 based on Figure 3 in the Phase 3 trial report. Using this method, the probability of having a subsequent SRE per cycle for zoledronic acid patients was estimated to be 16.7%. Further, the probability of having a subsequent SRE for denosumab patients was estimated based on the HR for time to first and subsequent SRE in the Phase 3 trial: 16.7% × 0.82 = 13.7%. 14 Transitional Probabilities to First or a Subsequent SRE Among Patients with Progression. Using clinical trial data, Tchekmedyian et al. (2010) showed that cancer progression was correlated with an increased risk of first SRE among patients with hormone-refractory prostate cancer (risk ratio [RR] = 2.14, P < 0.001). 19 The transitional probabilities to first SRE or a subsequent SRE among patients without progression were multiplied by the RR to estimate the corresponding transitional probabilities among patients with progression.
Transitional Probability to Disease Progression. Transitional probability to disease progression was estimated based on the median time to progression, which was 8.4 months for both arms in the Phase 3 trial. 14 Thus, assuming constant hazard, the study estimated the transitional probability to disease progression as 22.1% per cycle for both treatment arms.

Transitional Probability to SRE and Disease Progression.
Because the model assumed that the transition to first or subsequent SRE and the transition to disease progression were independent, transitional probability to SRE and disease progression was calculated as the product of the 2 transitional probabilities.
Transitional Probability from Progression to Death. The transitional probability from progression to death for the zoledronic acid arm was estimated so that the median overall survival predicted by the model was the same as the one reported in the Phase 3 trial, that is, 19.8 months. 14 Because the death rates in the 2 treatment arms did not significantly differ, 14 the transitional probabilities were assumed to be the same for both treatment arms in the base case.

Cost Inputs
Since this study was conducted from the perspective of a U.S. health care payer, only direct costs were considered for the model. These included costs associated with the treatment drugs (denosumab and zoledronic acid), SREs, disease progression, adverse events (AEs), and terminal care. All costs were inflated to 2010 U.S. dollars using the Medical Care Consumer Price Index (CPI) 20 and were discounted at 3% in the base case.
Costs for Treatment Drugs. Costs for denosumab and zoledronic acid treatments included drug acquisition costs, health care professional costs, and drug monitoring costs ( Table 1). The 4-week cost of treatment with zoledronic acid 4 mg was estimated to be $953, reflecting the sum of the wholesale acquisition cost of the 4 mg per 5 milliliter (ml) single-dose vial ($877.96, November 2010), up to 1-hour intravenous outpatient  Costs Associated with Progression. Costs associated with progression were estimated based on a claims study by Penson et al. (2004) estimating the effect of progression, defined as metastatic progression or prostate-specific antigen progression, on charges in prostate cancer patients. 24 Because the target population in the model already had metastatic prostate cancer, adjusted charges associated with prostate-specific antigen progression were used in this study. The study by Penson et al. reported that patients with prostate-specific antigen progression had health care charges of $69,321, compared with charges of $58,351 for patients without progression for a mean follow-up of 3.5 years. The costs associated with progression and nonprogression were estimated by applying the same CCR of 0.45 to the reported charges. Because in the base case we assumed that the probability of progression was the same for the 2 treatment arms, the cost associated with progression affected the results only in the sensitivity analysis, in which probability of progression was estimated using the median progression-free survival reported in the Phase 3 trial.
Costs for Terminal Care. Costs for terminal care were estimated based on a study using Medicare-Surveillance Epidemiology and End Results (SEER) data to examine the costs for the last year of life among elderly patients with different cancer types in the United States. 25  Costs Associated with AEs. AE costs were estimated based on the incidence rates presented at the 2010 American Society of Clinical Oncology (ASCO) conference (data available upon request). 26 In the published Phase 3 trial, other than the AEs of interest, only individual AEs experienced by at least 20% of patients in either treatment arm were reported, whereas the ASCO presentation included all AEs that were significantly different between the 2 treatment arms (based on the unadjusted P < 0.05). Therefore, we used the AEs presented at the ASCO presentation in the base-case model. Some AEs that are common in hormone-refractory prostate cancer patients, such as anemia, occurred at similar rates between the 2 treatment arms. Because inclusion of these AEs in the model would not have affected the results, they were not considered in the calculation of costs for AEs.
Costs associated with each AE were estimated based on the health resource use typical of real-world practice. For example, for AEs such as pyrexia, influenza-like illness, myalgia, chills, and muscle spasms, costs were calculated by summing costs for an outpatient physician visit and acetaminophen (obtained from ReadyPrice 2010), 15 which is commonly used in these bone metastasis. 5 The definition of SREs used in the study by Lage 5 Using these data, the mean annual charge per patient among patients with each specific SRE was estimated. For example, the annual charge of SRE per patient among those with therapeutic radiology was then estimated as $5,930 divided by 88.5% = $6,701. We further assumed that patients who experienced a specific type of SRE had the event only once during the 1-year time frame. For example, $6,701 was used as the mean charge per radiation to bone. The average charge per SRE was then estimated as the weighted average of the charge for each type of SRE, using the distribution of first on-study SRE types reported for each treatment arm in the Phase 3 trial as the weights. 14 For denosumab, the distribution was 19% for therapeutic radiology, 14% for pathologic fracture, 0.11% for bone surgery, and 3% for spinal cord compression. For zoledronic acid, the distribution was 21% for therapeutic radiology, 15% for pathologic fracture, 0.42% for bone surgery, and 4% for spinal cord compression. Using this method, we estimated average charges per SRE of $9,248 for zoledronic acid and $9,402 for denosumab (Table 1).
Because the current cost-effectiveness analysis was conducted from a payer perspective, charges were converted to costs of $4,892 and $4,973 (in 2010 dollars) for zoledronic acid and denosumab, respectively, by multiplying the charges with an estimated national average cost-to-charge ratio (CCR) for urban hospitals (0.45) and then inflating the converted costs to 2010 dollars. 20 The national average CCR was estimated as a weighted average of statewide average operating CCRs for urban hospitals in March 2000 22 using the total population in each state in the 2000 census 23 as weights. Data from the year 2000 were used to calculate the CCR because the data for SRE charges were obtained during the period from May 2000 to March 2005. 5 This CCR was applied to charges for all types of services related to SREs, including the services provided in physician offices. Further, because no separate cost estimates were reported for the first and subsequent SREs in the literature, the same cost was applied for all SREs. conditions. Outpatient physician costs were based on the 2010 Medicare physician fee schedule. 21 For cerebrovascular accidents, the cost associated with treating stroke (International

Classification of Diseases, Ninth Revision, Clinical Modification
[ICD-9-CM]: 434.91) 27 in a hospital setting was applied. 28 For cholelithiasis, the national average cost of lithotripsy was estimated as $17,430. 29 For dental-related AEs, such as tooth abscess, toothache, and osteonecrosis, costs of treatments that help relieve pain (e.g., ibuprofen) or treat tooth infections (e.g., amoxicillin) 30 along with a dental consultation fee 31 were applied. AEs indicating an SRE or disease progression, such as ilium fracture, increase in prostate-specific antigen, and thoracic vertebral fracture, were not included because they were already considered in the costs for the treatment of SREs or the costs associated with progression. A detailed description of how costs were estimated for each AE is in Table 2.

Model Outputs
Model outputs included costs and effectiveness for each treatment arm and incremental cost-effectiveness (total cost per SRE avoided) with denosumab compared with zoledronic acid.
Cost Outputs. Total direct costs were estimated by summing direct costs across all model cycles. Both total direct costs and costs for each component (drug costs and nondrug costs) were estimated. Drug costs were further classified into drug acquisition, health care professional, and drug monitoring costs; nondrug costs were further classified into disease-related costs (including costs associated with SREs and disease progression), terminal care costs, and AE costs. Incremental costs were estimated as the total cost differences between denosumab and zoledronic acid.
Effectiveness Outputs. Similar to cost outputs, the number of SREs was summed across all model cycles to estimate the total number of SREs. Because the model assumed that a maximum of 1 SRE could occur in each cycle, the total number of SREs was numerically equivalent to the total number of model cycles with an SRE. Incremental effectiveness was estimated as the difference in the total number of SREs between denosumab and zoledronic acid.
Incremental Cost-Effectiveness Output. The incremental cost-effectiveness output was total cost per SRE avoided if a patient was treated with denosumab versus zoledronic acid and was calculated by dividing the total incremental costs by the incremental effectiveness.

Sensitivity Analyses
One-way sensitivity analyses were performed to evaluate the impact of variations in key model inputs on the model results. Input parameters were varied over a specified range to assess their impact on the incremental total cost per SRE avoided over a 1-year and 3-year period. Probability of subsequent SRE, drug costs, and AE costs for zoledronic acid and denosumab were varied by ± 25% of base case value, and the remaining variables were varied using the reported 95% confidence intervals (CI). The charges of all 4 types of SREs were varied simultaneously based on the upper and lower limits of the 95% CIs reported by Lage et al. 5 In addition, discontinuation and adherence were also considered in our sensitivity analyses. Because of the difference in discontinuation and adherence rates in the real world compared with the clinical trial setting and the lack of evidence regarding treatment patterns and efficacy rates after patients discontinue treatment, we did not consider discontinuation and adherence in the base case analysis. In the sensitivity analysis, discontinuation was estimated based on the numbers of patients who discontinued in each arm from Figure 1 of the Phase 3 trial report, assuming a constant hazard of discontinuation. Adherence was estimated by dividing the median duration of exposure to study drugs (11.9 months to denosumab and 10.2 months to zoledronic acid) by the median time on study (12.2 months for denosumab and 11.2 months for zoledronic acid). In these analyses, we assumed that the efficacy remained the same after discontinuation. Additional sensitivity analyses were also conducted by applying rates of first SRE at different time points (i.e., 3, 6, 9, 12, and 27 months), based on Figure 2 in the Phase 3 trial report. These rates were used to re-estimate transitional probabilities from no SRE to first on-study SRE.
Multivariate probabilistic sensitivity analysis (PSA) was also conducted with a Monte Carlo simulation of 1,000 iterations. Model inputs with uncertainties and a large impact on the model results in the 1-way sensitivity analyses were included in the PSA (Table 3). The distributions of ICERs at 1 and 3 years were plotted in cost-effectiveness acceptability curves (CEACs), from which the probability of denosumab being cost-effective compared with zoledronic acid was assessed based on different willingness-to-pay (WTP) thresholds. The estimate of costs over the 3-year period showed that the cumulative drug cost for zoledronic acid 4 mg was $19,972 and that for denosumab 120 mg was $35,044 ( Table 4). The 3-year cumulative nondrug costs were $35,640 and $34,424 for zoledronic acid and denosumab patients, respectively. Denosumab treatment incurred an incremental drug cost of $15,071 but $1,216 lower nondrug costs. Total incremental costs were $13,856 for denosumab, and the incremental number of SRE was -0.27, leading to the incremental total cost per SRE avoided of $51,319 associated with the use of denosumab.

Sensitivity Analyses
The results in the 1-year 1-way sensitivity analyses ranged from a lower bound of $27,318 per SRE avoided to an upper bound of $161,680, comparing denosumab with zoledronic acid (Figure 2). The lower limit was estimated by lowering the drug costs for denosumab by 25% of the current value (from $1,672 to $1,254 per 4 weeks); the upper limit was obtained by applying the upper bound value of the 95% CI for the median time to first SRE for zoledronic acid (from 17.1 months to 19.4 months). Results of the 3-year 1-way sensitivity analysis ranged from $18,870 to $83,767 (data not shown in figure).
The 5 most sensitive input parameters included median time to first SRE for denosumab, median time to first SRE for zoledronic acid, denosumab drug costs, zoledronic acid drug costs, and relative risk of having an SRE associated with

Base Case
Over the 1-year period, the cumulative drug cost for zoledronic acid 4 mg was $10,960, whereas the cumulative drug cost for denosumab 120 mg was $19,230 (Table 4). Drug costs for zoledronic acid included $10,099 as drug acquisition costs, $777 as health care professional costs, and $84 as drug monitoring costs. Denosumab drug costs included $18,980 as drug acquisition costs and $250 as health care professional costs. Cumulative 1-year disease-related costs for zoledronic acid and denosumab patients were $13,585 and $13,097, respectively; cumulative 1-year terminal care costs were $2,649 for both treatments; and the cumulative 1-year costs for AEs were $334 and $365, respectively. The 1-year cumulative nondrug costs were $16,569 and $16,111 for zoledronic acid and denosumab patients, respectively. The total costs (drug costs and nondrug costs combined) incurred over 1 year were estimated at $27,528 for zoledronic acid and $35,341 for denosumab, resulting in a 1-year incremental total cost of $7,813 for denosumab compared with zoledronic acid. The estimated total number of SREs during the 1-year period was 0.49 for denosumab and 0.60 for zoledronic acid. This resulted in an incremental number of -0.11 SREs comparing denosumab versus zoledronic acid. Thus, the incremental total cost per SRE avoided with the use of denosumab was $71,027, compared with zoledronic acid.

Willingness-To-Pay (Cost Per SRE Avoided)
$51,319 at 1 and 3 years, respectively. The results were robust, with the majority of ICERs between $54,500 and $96,000 per SRE avoided in the 1-way sensitivity analyses. The model was most sensitive to the drug costs of denosumab and zoledronic acid and to the median time to first SRE for each treatment arm.
To further assess the robustness of the study results, we also conducted a simplified calculation using the published summary Phase 3 trial results. 14 The cumulative mean numbers of SREs per patient by month 12 were 0.60 for zoledronic acid and 0.49 for denosumab. With the assumptions that disease progression and death rates were exactly the same between the 2 arms and that the costs of AEs were also the same, the undiscounted incremental total costs would be $8,848 for denosumab over zoledronic acid (including $9,347 for incremental drug costs minus a $498 cost offset associated with reduced SREs). Thus, the incremental total cost per SRE avoided would be $80,439 ($8,848 divided by 0.11) in this simplified calculation, similar but slightly larger than the one obtained from the base-case Markov model.
Previous studies have used the same ICER metric to assess the cost-effectiveness of treatments that prevent or delay SREs, although the numbers are not directly comparable to results of the present study due to different clinical trial settings and disease areas. In one study of hormone-refractory prostate cancer patients with bone metastases, zoledronic acid had an incremental cost per SRE avoided of $18,485, compared with no treatment (converted to 2010 dollars for comparison). 6 In metastatic breast cancer, cost per SRE avoided using pamidronate compared with placebo was estimated at $6,379 with chemotherapy and $15,202 with hormonal therapy in 2010 dollars. 17 Compared with these numbers, the current estimate of $71,027 per SRE avoided seems to be high. With a WTP threshold of $70,000 per SRE avoided, the chance for denosumab to be cost-effective at 1 year was 49.5%.
Because there is no commonly accepted WTP threshold for cost per SRE avoided, we further conducted a cost-utility analysis using QALY as the effectiveness outcome. In the analysis, we applied the utilities associated with SRE versus no SRE estimated by Reed et al. 6 to the cycles with and without SREs, respectively. The analysis assumed that the utility effect of an SRE was limited to the 13-week cycle in which the SRE occurred. We did not consider the disutility associated with disease progression because it was not reported in the literature for hormone-refractory prostate cancer and because the base case assumed that there was no difference in progression between the 2 treatment arms. The results indicated that denosumab was associated with a total incremental cost of $3.91 million per QALY gained at the end of the first year and $2.77 million per QALY gained at the end of 3  Excluding the AE costs from the analysis resulted in incremental total costs per SRE avoided of $70,745 (1 year) and $51,204 (3 years). This showed that the results were not sensitive to the AEs. Considering discontinuation in the analysis resulted in 1-year and 3-year incremental total costs per SRE avoided of $63,735 and $40,411, respectively. Considering both discontinuation and adherence resulted in incremental total costs per SRE avoided of $67,596 and $42,813 at the end of 1 and 3 years, respectively. Applying rates of first SRE at different time points to estimate transitional probabilities resulted in a 1-year incremental total cost per SRE avoided ranging from $78,640 when using data at 3 months to $87,611 when using data at 27 months.
Results of the PSA showed that based on WTP thresholds of $70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the cases at 1 year, respectively, and it was cost-effective in 79.0%, 49.8%, and 4.1% of the cases at 3 years, respectively ( Figure 3).

■■ Discussion
Cost-effectiveness analyses have been increasingly applied to demonstrate economic value of different treatments from payers' perspectives. Although a new therapy could offer certain clinical advantages over existing treatments, the widespread adoption of a new treatment should be placed in the context of its impact on both clinical effectiveness and cost-effectiveness. In order to better inform U.S. payers about the potential value of denosumab in the treatment of hormone-refractory prostate cancer with bone metastases, we conducted the first economic evaluation to compare the cost-effectiveness of denosumab with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases, using a Markov model analysis from a U.S. payer perspective.
In the base case, the incremental total costs per SRE avoided comparing denosumab with zoledronic acid were $71,027 and Using this cycle length and constant transitional probability assumption, the model estimated that 44% of zoledronic acid patients and 38% of denosumab patients would have a first SRE at 1 year. The numbers were similar to those presented in the Phase 3 trial report (about 40% for zoledronic acid and 35% for denosumab). Third, the model was built using data from different sources to identify the costs and effectiveness inputs. For example, transitional probabilities to first SRE and subsequent SREs among patients with disease progression were estimated using the data from 2 different trials. 14,19 Costs were also obtained from different studies using different databases. While this approach is not uncommon in cost-effectiveness analysis, the inconsistencies between different study approaches and databases could lead to potential bias in the study results.
For example, cost per SRE was estimated using the annual charge for patients with at least 1 SRE in a retrospective analysis of a claims database. Assumptions had to be made in order to obtain this model input, such as (a) only 1 SRE occurred during the year, and (b) the national average CCR for urban hospitals was similar to the average CCR for SRE treatments. In addition, the original study by Lage et al. used ICD-9-CM and CPT-4 codes to identify the SREs. 5 The method has not been validated against a clinical dataset. We also assumed that the cost for a subsequent SRE was the same as the cost for a first SRE. These limitations will add uncertainties about the cost per SRE for the first and subsequent events and thus to the model results. However, the sensitivity analyses showed that using the 95% CIs for the annual charges of SREs reported in the Lage et al. study, the ICER varied only within ± $2,000 per SRE avoided compared with the base-case scenario.
Fourth, assumptions had to be made for inputs that were not directly available from the existing literature or public data. For example, costs associated with disease progression were obtained from a study that defined progression as prostatespecific antigen progression. 24 The relative risk of having a first SRE associated with disease progression was applied to the subsequent SREs because data for the latter are lacking. It is difficult to predict the direction of the bias given the uncertainty of these parameters. To address this limitation, 1-way sensitivity analyses were conducted by varying each of the model inputs within a specified range. Although the range of ICERs in the sensitivity analyses varied substantially, overall the findings were consistent, with ICER of denosumab versus zoledronic acid less than $50,000 in only 4 scenarios.
Fifth, when estimating the transitional probabilities, we assumed constant hazard instead of using other distributions, such as a Weibull distribution, that would have allowed for increasing or decreasing hazard over time. We chose the simplified functional form because we did not have access to patient-level data that would have allowed us to accurately and reliably estimate the parameters. In order to test how the comparison) were $239,255 comparing zoledronic acid with no treatment in hormone-refractory prostate cancer patients with bone metastases 6 and $108,200 and $305,300 comparing pamidronate with placebo in metastatic breast cancer patients receiving chemotherapy and hormone therapy, respectively. 17 A recent study by Snedecor et al. (2011) 32 estimated an incremental cost per QALY of $1.25 million comparing denosumab and zoledronic acid over a period of 27 months, using the Phase 3 trial on which the present study was conducted. Although the present study and the study by Snedecor et al. estimated different ICERs due to the different health states considered and model assumptions, both suggest that denosumab may not be a cost-effective alternative to zoledronic acid.
Constrained by budget, payers often face decisions about how to allocate limited resources to achieve maximum benefits among patients. A real-world observational study showed that only one-third of patients with high risk of recurrent SRE (i.e., with at least 1 SRE) received any bisphosphonate therapy. 33 The current study, along with the previous poster abstract report of an economic evaluation, 32 provides scientific evidence for payers to assess different treatment options and select a costeffective approach to extend appropriate treatments to a highrisk population.

Limitations
First, the economic evaluation was conducted based on a Markov model, which assumed that each patient transitioned between different health states. The study is subject to the common challenges of an economic evaluation, that is, oversimplification of the disease course that happens in the real world. However, Markov models are a common and useful approach to simulate disease progression. The Markov model in the present study was developed considering all major events relevant to the comparison of the 2 treatments (i.e., SRE, SRE history, progression, and death). An alternative approach is to conduct a cost-effectiveness analysis based on the actual drug use and outcomes observed in the Phase 3 trial. However, this approach requires more detailed information, such as actual drug dose consumed during the first year, than what was reported in the published trial.
Second, as in any economic model analysis, the results from this study are contingent upon the assumptions applied. Efforts were made in this study to maximize evidence as obtained from the existing literature in order to minimize the number of assumptions and select assumptions that most closely approximate the real world. Other than the standard Markov model assumption, a major assumption was that a maximum of 1 SRE could occur in each cycle of 13 weeks. The cycle length was defined to allow enough time to separate 2 distinct SREs and a relatively stable state within each cycle. It was supported by the literature, which reported that the mean time between the first and second type of SRE was approximately 3 months. 5 Economic Evaluation of Denosumab Compared with Zoledronic Acid in Hormone-Refractory Prostate Cancer Patients with Bone Metastases assumption affected our model results, we conducted sensitivity analyses to estimate the transitional probabilities based on the proportion of patients with first on-study SRE at different time points (3,6,9,12, and 27 months) in the Kaplan-Meier curve shown in Figure 2 of the published Phase 3 study report. 14 The ICERs ranged from $78,640 using data from 3 months to $87,611 using data from 27 months. Results from the sensitivity analysis showed that using median time to first SRE to estimate the transitional probabilities may not overestimate the ICER, even if the transition was assumed to be at a constant rate. Sixth, the model treated all SREs as the same type of event. In clinical practice, the nature of these events can be very different. Some SREs would lead to other SREs, for example, pathologic fracture may lead to surgery to bone. It may be interesting from a clinical perspective to examine the cost per pathologic fracture avoided.

■■ Conclusions
This economic evaluation is the first to compare the costeffectiveness of denosumab versus zoledronic acid in the prevention or delay of SREs in hormone-refractory prostate cancer patients with bone metastases. The base case showed that the incremental total costs per SRE avoided for denosumab were $71,027 over a 1-year period and $51,319 over a 3-year period, suggesting that denosumab may be a costly alternative to zoledronic acid. The conclusions were supported by the majority of sensitivity analyses. These findings could better inform payers regarding formulary inclusion and reimbursement in the treatment of patients with bone metastases in hormone-refractory prostate cancer.